PROJECT SUMMARY The development of pancreatic cancer vaccines is an area of intense investigation and considerable yet unfulfilled promise. The current paradigm is the development of pancreatic cancer vaccines targeting shared tumor antigens. We propose a conceptually innovative new paradigm: development of personalized pancreatic cancer vaccines targeting neoantigens. We have studied the dynamic relationship between the immune system and cancer in detail, ultimately proposing the cancer immunoediting hypothesis. Recently, we have focused on identifying the antigens recognized by the immune system during cancer immunoediting, and in response to cancer immunotherapies such as checkpoint blockade. These studies demonstrate that neoantigens are important tumor rejection antigens, providing strong support for our neoantigen vaccine strategy. We have developed, optimized and validated next-generation sequencing and epitope prediction algorithms to identify and prioritize neoantigens, and will use these algorithms in the proposed clinical trial. Our initial clinical experience targeting neoantigens in patients with melanoma confirms that neoantigen vaccines are capable of generating neoantigen-specific T cell responses. We will test the safety and immunogenicity of personalized DNA vaccines targeting pancreatic cancer neoantigens in a phase 1 clinical trial. In parallel studies, we will test the ability of immune modulators to enhance vaccine efficacy in preclinical models of minimal residual disease. These studies will provide the rationale for phase 2 clinical trials of next generation personalized vaccines, and/or combination therapies. Specific Aim 1: A phase 1 clinical trial of a personalized pancreatic cancer DNA vaccine strategy in patients who have completed adjuvant therapy for pancreatic cancer. Specific Aim 2: Test the ability of personalized pancreatic cancer DNA vaccines targeting CD8?+ dendritic cells to enhance antitumor immunity in a preclinical model of minimal residual disease. Specific Aim 3: Test the ability of CCR2 inhibitors to enhance the response to personalized pancreatic cancer vaccines in a preclinical model of minimal residual disease.